This application is submitted in response to the Program Announcement Neurodevelopment and Neuroendocrine signalling in Adolescence: Relevance to Mental Health (PA-09-008). The primary objective of our research is to understand how rising levels of testosterone during male adolescence affect the axon. The secondary objective is to evaluate the possible impact of such effects on the risk of psychopathology during male adolescence. The focus on the axon, a key element in long-range cell-to- cell communication in the nervous system, is motivated by the known impairment of neural connectivity in disorders emerging during adolescence and young adulthood, including depression and schizophrenia. To reach our goal, the proposed research sets the following four specific aims. (1) To evaluate whether or not the timing & dynamics of sexual maturation during early and mid-adolescence predicts structural properties of white matter during late adolescence. To achieve this aims, we will employ multi-modal magnetic-resonance imaging (MRI) of white matter in a large number (n=500) of 18-year old male adolescents selected from a unique longitudinal birth-cohort established in England in early 1990's, namely the Avon Longitudinal Study of Parents and Children (ALSPAC). The timing & dynamics of sexual maturation will be indexed by the age of puberty onset and changes in testosterone levels throughout adolescence, i.e. using information collected in this cohort over the past 10 years. (2) To evaluate the moderating effects of genes involved in testosterone signalling and/or metabolism on the predicted relationship between testosterone levels and structural & functional propertise of white matter. This aim will be achieved by genotyping the 500 male adolescents for functional polymorphisms in the androgen-receptor (AR) gene and the 5-alpha reductase gene; (3) To evaluate whether experimental manipulations of testosterone levels during puberty affect functional and morphological properties of the axon. This aim will be achieved by studying male rats following real or sham castration, with or without supplementation of testosterone. In this animal model, we will measure two main phenotypes: (a) axonal transport using in vivo Mn++ MR imaging at 7 T; and (b) axonal caliber and myelin thickness assessed ex vivo with electron microscopy; and (4) We will evaluate possible relationship between the timing & dynamics of sexual maturation and the risk of psychopathology and assess whether puberty-related changes in white matter modulate this relationship. This aim will be achieved using the existing longitudinal information about puberty and psychopathology collected in the last 10 years in the ALSPAC participants, and by an assessment of the risk of psychopathology at the time of an MR acquisition, i.e. at the age of 18 years. The above research program integrates population neuroscience (Aims 1, 2 & 4) with experimental neuroscience (Aim 3), with the ultimate goal to understand how inter-individual variations in the maturation of white matter during male adolescence might affect mental health.